Xanthone carboxylic acids and derivatives

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions are also disclosed. 7Acetylxanthone-2-carboxylic acid is illustrated as representative of the class.

United States Patent 91 Pfister et al.

[11] 3,818,042 [451 June 18, 1974 XANTHONE CARBOXYLIC ACIDS ANDDERIVATIVES inventors: Jurg R. Pfister, Los Altos; Ian T.

Harrison; John H. Fried, both of Palo Alto, all of Calif.

Assignee: Syntex (U.S.A.), Inc., Palo Alto,

Calif.

Filed: June 5, 1972 Appl. No; 259,853

Related US. Application Data Continuation-impart of Ser. No. 217,383,Jan. 12, 1972, which is a continuation-in-part of Ser. No. 162,696, July14, 1971, abandoned.

US. Cl. 260/335, 424/283 Int. Cl C07d 7/44 Field of Search 260/335 [56]References Cited UNITED STATES PATENTS 3,706,768 12/1972 Bays 260/335Primary ExaminerNorma S. Milestone Attorney, Agent, or FirmEvelyn K.Merker; Walter H. Dreger 14 Claims, N0 Drawings XANTHONE CARBOXYLICACIDS AND DERIVATIVES sential ingredient in the treatment of symptomsassociated with allergic manifestations, for example, asthmaticconditions.

In a first aspect, the present invention relates to novel xanthonecarboxylic acid compounds selected from those represented by thefollowing formulas:

ll ii A o OH R- A o 0 OH and the pharmaceutically acceptalE non-toxicesters, amides and salts thereof; wherein each R is a group selectedfrom those of the formulas:

in which R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl,tetrahydropyran-2-yl, tetrahydropyran-4-yl,4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12atoms, and R is hydrogen, lower alkyl or cycloalkyl, R is hydrogen;lower alkyl; cycloalkyl; phenyl; substituted phenyl in which thesubstituent is halo, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic grouphaving five or six total members, one or two of which are selected fromnitrogen, oxygen, and sulfur.

Thus included within the scope of the present invention are the C5 andC-7 secondary and tertiary lhydroxyalkyl substitutedxanthone-Z-carboxylic acid compounds and the hydroxy esters (preferablyacetoxy) and hydroxy ethers (preferably methoxy) thereof and the C-5 andC7 acyl substituted xanthone-Z- carboxylic acid compounds.

In a second aspect, the present invention is directed to a method usefulfor relieving symptoms associated with allergic manifestations such asare brought about by antigen-antibody (allergic) reactions. In therelief of these symptoms, the method hereof serves to inhibit theeffects of the allergic reaction when administered in an effectiveamount. While not intending to be bound by any theoretical mechanism ofaction, the method hereof is believed to operate by inhibiting therelease and/or the action of toxic products, e.g. histamine,S-hydroxytryptamine, slow releasing substance (SRS-A), and other, whichare produced as a result of a combination of specific antibody andantigen (allergic) reaction. These properties make the subject compoundsparticularly useful in the treatment of various allergic conditions.

This aspect of the present invention thus relates to a method useful forinhibiting the effects of the allergic reaction which comprisesadministering an effective amount of a compound selected from thoserepresented by the following formulas:

o o H 00 OH R- o 0 OH JAL M93 and the pharmaceutically acceptablenon-toxic esters, amides, and salts thereof; wherein each R is a groupselected from those of the formulas:

in which R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl,tetrahydropyran-Z-yl, tetrahydropyran-4-yl,4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12carbon atoms, and R is hydrogen, lower alkyl or cycloalkyl, and R ishydrogen; lower alkyl; cycloalkyl; phenyl, substituted phenyl in whichthe substituent is halo, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic grouphaving five or six total members, one or two of which are selected fromnitrogen, oxygen, and sulfur, or a pharmaceutically acceptable non-toxiccomposition incorporating said compounds, esters, amides or salts as anessential ingredient.

The compounds of the present invention are also smooth muscle relaxants,e.g., bronchial dilators, and are therefore useful in the treatment ofconditions in which such agents may be indicated, as for instance, inthe treatment of broncho constriction. The compounds of the presentinvention are also vasodilators and are therefore useful in thetreatment of conditions in which such agents may be indicated, as forinstance, in renal and cardiac disorders.

The present invention, in a third aspect, is directed to pharmaceuticalcompositions useful for inhibiting the effects of the allergic reactionscomprising an effective amount of a compound selected from thoserepresented by the following formulas:

and the pharmaceutically acceptable esters, amides, and salts thereof;wherein each R is a group selected fromthose of the formulas:

t/ is in which R is hydrogen, lower alkyl, cycloalkyl,tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl, tetrahydropyran-4-yl,4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12carbon atoms, and R is hydrogen, lower alkyl or cycloalkyl, and R ishydrogen; lower alkyl; cycloalkyl; phenyl; substituted phenyl in whichthe substituent is halo, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic grouphaving five or six total members, one or two of which are selected fromnitrogen, oxygen, and sulfur, in admixture with a pharmaceuticallyacceptable nontoxic carrier.

In the practice of the method of the present invention, an effectiveamount of a compound of the present invention or pharmaceuticalcompositions thereof, as defined above, is administered via any of theusual and acceptable methods known in the art, either singly or incombination with another compound or compounds of the present inventionor other pharmaceutical agents, such as antibiotics, hormonal agents,and so forth. These compounds or compositions can thus be administeredorally, topically, parenterally, or by inhalation and in the form ofeither solid, liquid, or gaseous dosages including tablets, suspensions,and aerosols, as discussed in more detail hereinafter. The administra--tion can be conducted in single unit dosage form with continuous therapyor in single dose therapy ad libitum. In the preferred embodiments, themethod of the present invention is practiced when relief of symptoms isspecifically required, or perhaps, imminent; however, the method hereofis also usefully practiced as continuous or prophylactic treatment.

In view of the foregoing as well as in consideration of the degree orseverity of the condition being treated, age of subject, and so forth,all of which factors being determinable by routine experimentation byone skilled in the art, the effective dosage in accordance herewith canvary over a wide range. Generally, an effective amount ranges from about0.005 to about 100 mg. per kg. of body weight per day and preferablyfrom about 0.01 to about 100 mg. per kg. of body weight per day. Inalternate terms, an effective amount in accordance herewith generallyranges from about 0.5 to about 7000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids, or gases. Thus, the compositions cantake the form of tablets, pills, capsules, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, and the like.The carriers can be selected from the various oils including those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipientsinclude starch, cellulose, talc, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesiumstearate, sodium stearate, glyceryl monosterate, sodium chloride, driedskim milk, glycerol, propylene glycol, water, ethanol, and the like.Suitable pharmaceutical carriers and their formulation are described inRemingtons Pharmaceutical Sciences" by E. W. Martin. Such compositionswill, in any event, contain an effective amount of the active compoundtogether with a suitable amount of carrier so as to prepare the properdosage form for proper administration to the host.

The compounds of the present invention demonstrate activity asinhibitors of the effects of the allergic reaction as measured by testsindicative of such activity involving passive cutaneous anaphylaxis assubstantially described, for example, by J. Goose et al., Immunology,16, 749 (1969).

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence:

Sequence A (a) boom (30012 halo i (2) COR coon A 00R e i O/ V\O (4) 10OH wherein R is lower alkyl, preferably methyl; R is acyl; and halo isbromo. chloro. fluoro. or iodo, preferably bromo.

With reference to the above sequence, an ortho or para substituted (Rphenol l is condensed with the l,3-dicarbo(lower)alkoxy-4-halobenzenecompound (2) in the presence of cuprous oxide optionally in organicliquid reaction medium, preferably an organic amide such as dimethylacetamide, dimethyl formarnide, N-methyl pyrrolidone, tetramethylurea,and so forth, to prepare the corresponding l,3-dicarbo(lower- )alkoxy-4-(oor p-subsituted phenyloxy)-benzene compound (3).

The reaction is preferably conducted in an inert organic reactionmedium, such as those listed above, or suitable mixtures of one or moreof such mediumv The reaction is further conducted at temperaturesranging from about to about 220C, preferably about from to 200C, and fora period of time sufficient to complete the reaction, ranging from abouttwo hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of thesubstituted phenol per mole of the dicarbo(lower)carboxyhalobenzene perhalf mole of cuprous oxide. However, the amounts of the reactants to beemployed are not critical, some of the desired com pound (3) productbeing obtained when employing any proportions thereof. In the preferredembodiments, the reaction is conducted by reacting from about one toabout three moles of the substituted phenol compound with about from oneto about 1.2 moles of the dicarbolower)carboxyhalobenzene compound inthe presence of from about 0.5 to about 0.6 moles of the cuprous oxide.The inert organic reaction medium, if employed, is used in solventamounts.

Thereafter, the prepared compound (3) is base bydrolyzed to give thecorresponding l,3-dicarboxy-4-(oor p-substituted phenyloxy )-benzene(4). The base hydrolysis conditions can be any employed conventionallyin the art. Generally, the hydrolysis reaction is conducted using analkali metal hydroxide at about 50 to about 90C and for a period of timesufficient to complete the reaction, ranging from about minutes to about60 minutes, preferably in the presence of inert organic reaction mediasuch as those normally employed in organic chemical reactions of thistype, e.g., aqueous alkanol solutions. Although two moles of base arerequired per mole of compound (3), the amounts employed are not criticalto produce the desired bydrolysis. Preferably from about 3 to about 5moles of base are employed per mole of compound (3) and the -reactionmedia, if employed, is used in solvent amounts.

The thus prepared diacid compound (4) is then cyclized with phosphorylchloride, thionyl chloride, sulfuric acid, hydrogen fluoride, orpreferably, polyphosphoric acid (PPA), to give the corresponding 5- or7- substituted xanthone-Z-carboxylic acid compound (5). The reaction ispreferably, but optionally, conducted in an inert organic reactionmedium including those usudimethylsulfoxide, sulfolane, benzene,toluene, and so forth. The reaction is further conducted at temperaturesranging from about 60 to about 180C, and for a period of time sufiicientto complete the reaction ranging from about 15 minutes to about 90minutes.

Although the reaction consumes the'reactants on the basis of one mole ofcompound (4) per mole of cyclizing reagent, the reaction can beperformed using any proportions of reactants. In the preferredembodiments, however, the reaction is conducted using from about toabout 50 moles of the cyclizing reagent per mole of starting compound(4).

The compounds of the present invention in the 5 or 7-(secondaryhydroxyalkyl)-xanthone-2-carboxylic acid series are prepared from thecorresponding 5- or 7-acyl compounds, prepared as described above. The5- or 7-acylxanthone-2-carboxylic acids are converted to thecorresponding acid ester such as with alkyl iodide under basiccondition. The acyl ester is then re- 20 duced such as with sodiumborohydride to give the 5- or 7-(secondaryhydroxyalkyl)-xanthone-2-carboxylic acid ester which can be hydrolyzedto the acid.

The 5- or 7-(tertiary hydroxyalkyl)-xanthone-2- carboxylic acids hereofare prepared by treating the 5- or 7-acylxanthone carboxylic acid esterswith a lower alkyl or cycloalkyl Grignard reagent followed by hydrolysisof the ester.

Certain of the compounds of the present invention can be prepared inaccordance with the following reacally employed in organic chemicalreactions, such as tion sequence:

Sequence B A COOH A CODE OH 0 0 o A kc: H 000R 4 000R acid (7). Thiscompound is conventionally esterified 20 (R by means known to thoseskilled in the art, for example, by treatment of the acid withdiazoalkane or with alkanol and sulfuric acid The resultant ester (8) isthen acylated under Friedel-Crafts conditions with an acid chloride inthe presence of aluminum chloride to 25 give h sqtrs qviisiras Q PPPILMQQi-V The resultant compound (9) is oxidized, under known Jonesconditions, to give the corresponding 7-acylxanthone-Z-carboxylateesters (10), which can be hydrolyzed, as described above, to give the 307-acylxanthone-2-carboxylic acid compounds (15).

Compounds (10) can also be reduced, such as by the known method usingsodium borohydride, to give the R OH 0 o 0 l: l )K 4 COOH O 00011 0 0/ lV (14) M wherein i' is 1 exclusive of hydrogen 2 is 2 corresponding7-(secondary hydroxyalkyl)-xanthone- Z-carboxylate esters (l l) whichcan be hydrolyzed to the acid products (13).

Compounds 10) can also be treated with alkyl or cy- Pi llQll r l E d a et under l 5 Crignard reactio-n conditions, to give the correspond ing7-(tertiary hydroxyalkyl)-xanthone-2-carboxylate esters (12) which canbe hydrolyzed to the acid products (14).

Alternatively, the compounds of formula (9) can be reduced or treatedwith Grignard reagent, as described above, to prepare the corresponding7-(secondary and tertiary hydroxyalkyl) xanthene compounds, These can beacylated via conventional secondary and tertiary acylation techniques togive the corresponding esters which are oxidized under Jones conditionsto prepare the corresponding 7-( secondary and tertiaryacyloxyalkyl)-xanthone-2-carboxylic acid esters which, when hydrolyzedunder base conditions, gives the corresponding 7-(secondary and tertiaryhydroxyalkyl)-xanthone- 2carboxylic acid products (13 and 14),

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence:

Sequence 0 i ii 000w C10, coo R3 i u 000R OHC coon ii OHC A 00 OH Withreference to the above reaction sequence, xanthene-Z-carhoxylic acidester (8) is reacted with chloroacetyl chloride under Friedel-Craftsconditions.

to give compound (16). This compound is then oxidized as described aboveto give the corresponding xanthone (17) which is reduced as describedabove to give the hydroxy compound (18). The resultant compound istreated with sodium hydride in dimethylformamide to oxide the exidoderivative (19). This compound is treated with periodic acid or theperchloric acid and sodium periodate to give the 7-formylxanthone-2-carboxylate ester (20) which is hydrolyzed to the acidproduct (21 An alternative method for the preparation of certain of theC-5 substituted compounds hereof is illustrated by the followingsequence:

Sequence D" 'W 7 I CHI COOR3 /CH; 000w 00011 (23) halo J 2 coon 0 llCOOH COOH i o din oooH CH1 R2 R24 2 2O 2 2 7 "2204.21 "V v A coon CO0H=0 H-OH o A l coon (5-011 R: R1 (28) esters are oxidized with chromiumtrioxide in acetic acid-acetic anhydride to give the S-acyl compounds(26) which are reduced or treated with Grignard reagent as abovedescribed to give the respective 5- (secondary and tertiaryhydroxyalkyl)-xanthone-2- carboxylic acid products (27 and 28).Alternative to the above procedure, the 5-substituted xanthone-Z-carboxylic acid (25) can be converted to its corresponding ester and ittreated with N-bromosuccinimide to prepare the correspondingS-(substituted bromomethyl) compound (i.e.,

which can be converted to the corresponding alcohol upon treatment withaqueous base, to give the product acids (27).

The compound 5-methylxanthone-2-carboxylic acid,

prepared as described in Sequence A (1 5) from omethylphenol, can beoxidized under known Thiele conditions to give the corresponding'5-formylxanthone-Z-carboxylic acid. This method is also useful forcarboxylic acid.

A particularly preferred method for the preparation of certain of thecompounds hereof is represented as follows:

preparing 7-formylxanthone-2- COOH O OH

wherein R is as defined above.

With reference to the above sequence, an appropriate phenol (29) istreated with 1,3-dimethyl-4-halo- (preferably iodo) benzene (30), asdescribed above, to prepare the corresponding 1,3-dimethyl-4-phenyloxybenzene (31) This compound is then oxidized such as with potassiumpermanganate in aqueous t-butanol, to give the correspondingl,3-dicarboxy-4-phenyloxybenzene (32). This compound is then cyclized,as described above, to give the corresponding xanthone-Z- carboxylicacid (33) which can be modified as described above to prepare theproduct C-5 or C-7 substituted compounds hereof.

The carboxylic acyl esters of the secondary and tertiary hydroxy alkylsubstituted compounds (i.e. R=carboxylic acyl) are prepared as describedabove or by secondary and tertiary alcohol esterification methods knownper se. One such method involves treating the products represented byFormulas l3) and (27) with a carboxylic acid chloride or carboxylic acidanhydride in the presence of a base, preferably pyridine, attemperatures ranging from about 60 to about 90C and for a period of timeranging from about 1 to about 2 hours to give the correspondingsecondary carboxylic acyloxy alkyl substituted xanthone-2- carboxylicacid compound. Likewise, by treating the products of Formulas (l4) and(28) with a carboxylic acid chloride and dimethylaniline intetrahydrofuran or with a mixed carboxylic acid, p-toluenesulfonic acidanhydride, the corresponding tertiary carboxylic acyloxy alkylsubstituted xanthone-2-carboxylic acid compounds are prepared. SeeHarrison and Harrison, Compendium of Organic Synthetic Methods,Wileylnterscience, New York (197l) 281 and 2 and the references citedthereon.

The alkyl and cycloalkyl ethers of the secondary hydroxyalkyl series(R=alkyl, cycloalkyl) are prepared by treatment of the xanthone acidester with the appropriate alkyl or cycloalkyl halide and sodium hydridein, e.g. dimethylformamide, followed by hydrolysis, as described above.The etherification reaction is conducted at from about 50 to about 80Cand for from about 1 to about 5 hours. In the tertiary alcohol series.the alkyl and cycloalkyl ethers are prepared by treating the precursoracyl compound, e.g. 7-acetylxanthone-2- carboxylic acid ester, underGrignard conditions, as described above, but in the presence ofappropriate alkyl or cycloalkyl iodide or bromide andhexamethylphosphoramide to concomitantly afford the alkyl or cycloalkylether of the tertiary alcohol, followed by hydrolysis as describedabove. See Harrison and Harrison, Compendium of Organic SyntheticMethods, Wileylnterscience, New York (1971), 323 and the referencescited thereon.

The t-butoxy ethers are prepared by treating the alcohol with isobutenein the presence of boron trifluoride and phosphoric acid in, e.g.methylene chloride, at temperatures of from about 10 to about 30C andfor from 10 to about 24 hours, or more, followed by hydrolysis of theacid ester group, as described above.

The tetrahydrofuran-Z-yloxy and tetrahydropyran-Z- yloxy ethers in thesecondary and tertiary alcohol series are prepared by treatment withdihydrofuran or dihydropyran in the presence of p-toluenesulfonic acidand organic reaction medium, e.g. benzene, to about room temperature upto reflux, for from about two to about five days, followed by hydrolysisof the acid ester, as described above.

The 4-alkoxytetrahydropyran-4-yloxy ethers in the secondary and tertiaryalcohol series are prepared by treatment of the alcohol with4-alkoxy-5,6-dihydro-2H- pyran, as described above for the preparationof the furanyl and pyranyl ethers, followed by acid ester hydrolysis.Treatment of the 4-alkoxytetrahydropyran-4- yloxy ether with aluminumchloride and lithium aluminum hydride in organic reaction medium affordsthe corresponding tetrahydropyran-4-yloxy ethers which are oxidized togive the corresponding ethers in the xanthone acid series. The lattercan be directly prepared by treating the alcohol with4-bromotetrahydropyran and base. See Harrison and Harrison, Compendiumof Organic Synthetic Methods, Wileylnterscience, New York I971 l29 andthe references cited thereon.

The acid esters of the xanthonc-Z-carhoxylic acids hereof are preparedas described above (cg. 7 8) upon treatment of the acid with etherealdiazoalkane such as diazomethane and diazoethane or with the desiredlower alkyl iodide in the presence of lithium carbonate at roomtemperature or with the desired lower alkanol in the presence of a traceof sulfuric acid at reflux. The glycerol esters are prepared by treatingthe acid with thionyl chloride followed by treatment with a suitablyprotected ethylene glycol or propylene glycol (e.g., solketal) inpyridine, and hydrolyzing the protecting group of the ester thus formedwith dilute acid. In the sulfo series, the carboxylic acid esters arepreferably prepared with the desired lower alkanol in the absence ofacid catalyst.

The amides of the xanthone-Z-carboxylic acids hereof are prepared bytreatment of the acids with thionyl chloride followed by treatment withanhydrous ammonia, alkyl, amine, dialkylamine, dialkylaminoalkylamine,alkoxyalkylamine, or phenethylamine.

The salts of the xanthone-2-carboxylic acids hereof are prepared bytreating the corresponding acids with pharmaceutically acceptable base.Representative salts derived from such pharrnaceutically acceptablebases are sodium, potassium, lithium, ammonia, calcium, magnesium,ferrous, ferric, zinc, manganous, aluminum, manganic, the salts oftrimethylamine, triethylamine, tripropylamine, B-(dimethylamino)ethanol,triethanolamine, fi-(diethylaminmethanol, arginine, lysine, histidine,N-ethylpiperidine. hydrabamine, choline, betaine, ethylenediamine,glucosamine, methyl glucamine, theobromine, purines, piperazine,piperidine, polyamine resins, caffeine, procaine or the like. Thereaction is conducted in an aqueous solution, alone or in combinationwith an inert, water miscible organic solvent, at a temperature of fromabout 0C to about C, preferably at room temperature. Typical inert,water miscible organic solvents include methanol, ethanol, isopropanol,butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal saltsare prepared, such as the calcium salts or magnesium salts of the acidsthe free acid starting material is treated with about one half molarequivalent of pharmaceutically acceptable base. When the aluminum saltsof the acids are prepared about one third molar equivalent of thepharmaceutically acceptable base are employed.

In the preferred embodiment of the present inven tion, the calcium saltsand magnesium salts of the acids are prepared by treating thecorresponding sodium or potassium salts of the acids with at least onehalf molar equivalent of calcium chloride or magnesium chloride,respectively, in an aqueous solution, alone or in combination with aninert water miscible organic solvent, at a temperature of from about 20Cto about 100C.

In the preferred embodiment of the present invention, the aluminum saltsof the acids are prepared by treating the acids with at least one thirdmolar equivalent of an aluminum alkoxide, such as aluminum triethoxide,aluminum tripropoxide and the like, in a hydrocarbon solvent, such asbenzene, xylene, cyclohexane, and the like at a temperature of fromabout 20C to about ll5C.

The starting compounds for use in the present invention are known andcan be prepared in accordance with known procedures. Thus, the l ,3-dicarbo(lower)alkoxy-4-halobenzene starting compounds (2) areconveniently prepared by oxidizing 13 l,3-dimethyl-4-halobenzene(4-halo-m-xylene) with potassium permanganate, as described above (31-32), followed by conventional esterification. The

or p-acylphenols l are conveniently prepared by performing aFriedel-Crafts reaction with phenol to give the desired acylphenolcompounds which can be sepaphenol starting compounds, are prepared, forexample,

by selectively esterifying hydroxybenzoic acid with methanol and a traceof sulfuric acid or with lithium carbonate and methyl halide indimethylformamide. The resultant hydroxybenzoate ester is thenconventionally alkylated with lower alkylhalide and potassium carbonatefollowed by selective hydrolysis of the ester of the carboxylic acidgroup and conversion to the acid chloride with, e.g., thionyl chloride.

In the present specification and claims, by the term lower alkyl" isintended a lower alkyl group containing one to eight carbon atomsincluding straight and branched chain groups, for example, methyl,ethyl, n-

propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 25

n-pentyl, isopentyl, sec-pentyl, t-pentyl, n-hexyl, npentyl, n-octyl,isooctyl. The term cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. By the term lower alkoxy is intended thegroup O-lower alkylwherein lower alkyl is as defined above. By the termlower alkylthio is intended the group S-lower alkyl" wherein lower alkylis as defined above. The term substituted phenyl includes p-substitutedphenyl. The term monocyclic aromatic heterocyclic group includespyridyl, pyridazinyl, py- 35 rimidinyl, pyrazinyl, imidozolyl, furanyl,thiophenyl, pyrrolyl, isoxazolyl, and oxazolyl.

By the term pharmaceutically acceptable, non-toxic esters, amides, andsalts is respectively intended an alkyl or glycerol ester; anunsubstituted, monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl, orphenethyl substituted amide and a salt as defined above.

The term carboxylic acyl," as used herein, refers to thosephysiologically acceptable acyl groups, conventionally employed in thepharmaceutical art, preferably hydrocarbon carboxylic acyl. Included areacetate, propionate, butyrate, trimethylacetate, valerate,methylethylacetate, caproate, t-butylacetate, 3- methylpentanoate,enanthate, caprylate, triethylacetate, pelargonate, decanoate,undecanoate, benzoat'e, phenylacetate, diphenylacetate,cyclopantylpropionate, methoxyacetate, aminoacetate,diethylaminoacetate, trichloracetate, B-chloropropionate, bicyclo[2.2.-2 ]0ctane-1 -carb0xylate, adamantoate, dihydrogen phosphate. dibenzylphosphate, sodium ethyl phosphate, sodium sulfate, sulfate, and thelike.

In the secondary and tertiary hydroxyalkyl series the compounds maypossess a chiral center. The methods hereof generate each of the d and land d1 forms and each is thus included within the scope hereof. Ifdesired, the isomers can be separated by conventional means such asforming the alkaloid salts of the products.

and employing fractional crystallization.

The nomenclature herein is employed in accordance with ChemicalAbstracts 56 Subject Index (1962, January-June).

The following examples illustrate the method by which the presentinvention can be practiced.

EXAMPLE I A mixture of 3.9 g. of 1,3-dicarbomethoxy-4- bromobenzcne,2.85 g. of p-acetylphenol, 1.1 g. of cuprous oxide, and 25 ml. oftetramethylurea is heated to 5 I65C and maintained thereat with stirringfor 18 hours under a nitrogen atmosphere. After this time, the reactionmixture is diluted with water and extracted with ether. The extracts aredried and evaporated to give I,-3-dicarbomethoxy-4-(p-acetylphenyloxy)-benzene.

I,3-Dicarbomethoxy-4-( p-acetylphenyloxy )-benzene (3.5 g.) is dissolvedin 50 ml. of ethanol and the mixture treated with ml. of 4 percentaqueous potassium hydroxide solution. The reaction mixture is refluxedfor minutes, concentrated under reduced 15 pressure, and acidified withdilute hydrochloric acid.

The solid collected upon filtration is washed with water and dried togive l,3-dicarboxy-4-(p-acetylphenyloxy)- benzene which isrecrystallized from ethanol-water.

A solution of 3.2 g. of l,3-dicarboxy-4-(p-acetylphenyloxy)-benzene in30 ml. of concentrated sulfuric acid is warmed to 80C. The mixture isthen allowed to stand at room temperature for 16 hours after which timeit is poured into ice water, filtered, washed and dried to give7-acetylxanthone-2-carboxylic acid which is recrystallized fromtetrahydrofuran-ethanol. The foregoing method can also be employed usingan alternative 1,3-carboloweralkoxy-4-halo starting compound such as1,3-dicarbomethoxy-4-chloro or iodo benzene, 1,3-dicarboethoxy-4-fluorobenzene, 1,3-dicarboethoxy-4-bromo benzene, and the like, with similarresults.

In a similar manner, the above described reactions can be conductedutilizing an alternate p-acyl phenol starting material to give thecorresponding 7-acyl-xanthone-2-carboxylic acid products, e.g.,7-formylxanthone-2-carboxylic acid, 7- propionylxanthone-2-carboxylicacid, 7-nbutyrylxanthone-2-carboxylic acid,7isobutyrylxanthone-Z-carboxylic acid, 7-n-pentanoylxanthone-2-carboxylic acid, 7-isopentanoylxanthone-2-carboxylic acid,7-sec-pentanoylxanthone-2-carboxylic acid,7-tcyclopropylcarbonylxanthone-Z-carboxylic acid, 7-

cyclobutylcarbonylxanthone-2-carboxylic acid, 7-cyclopentylcarbonylxanthone-Z-carboxylic acid, 7-cyclohexylcarbonylxanthone-Z-carboxylic acid, 7-haIoacetylxanthone-2-carboxylic acid, 7-

acid, 7-substituted acid, and 7- benzoylxanthone-2-carboxylicbenzoylxanthone2-carboxylic heterocycliccarbonylxanthone-2-carboxylicacid.

The procedure of Example I is repeated using the appropriate o-acylphenolstarting compounds to prepare the corresponding 5-substitutedxanthone-Z-carboxylic acid, to wit, 5-formylxanthone-2-carboxylic acid,

0 5-acetylxanthone-2-carboxylic acid, 5- propionylxanthone-Z-carboxylicacid, 5-nbutyrylxanthone-2-carboxylic acid, 5

isobutyrylxanthoneQ-carboxylic acid, and so forth.

EXAMPLE 2 To a solution of 25 grams of xanthone-2-carboxylic acid(prepared as described in Example 1 from 1.3-dicarbomethoxy-4-bromobenzene and phenol) in 200 ml. of triethyleneglycol are added 18 g. of potassium hydroxide and 12.1 g. of 95 percenthydrazine. The resultant mixture is heated to reflux (155C) andmaintained thereat for 1 hour. The distillate is removed and thetemperature is held at a temperature of about 200C for 2 hours. Themixture is then cooled to 68C and 200 ml. of water is added and theresultant solution poured into 1 10 ml. of water containing 60 ml. ofconcentrated hydrochloric acid. The resultant mixture is heated to 90C,cooled to room temperature and filtered to give xanthene-2-carboxylicacid.

Twenty-six Grams of xanthene-Z-carboxylic acid is added to 400 ml. ofabsolute methanol. To the resultant solution are added 18 ml. ofconcentrated sulfuric acid and the mixture is then heated at reflux forabout 2 hours. The mixture is then cooled to 40C and sufficient water isadded to bring the total volume to 1400 ml. The resultant mixture isthen filtered to give methyl xanthene-Z-carboxylate.

A mixture of 13.0 g. of methyl xanthene-Z- carboxylate in 200 ml. ofdichloroethane is cooled to C and to the cooled solution are added 4.95ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. Theresultant solution is stirred at room temperature for 1.75 hours. Afterthis time, the solution is poured into a mixture of 300 g. of ice, 700ml. of water and 20 ml. of concentrated hydrochloric acid. The mixtureis then extracted with three 500 ml. portions of methylene chloride. Thecombined extracts are washed with percent aqueous potassium hydroxidesolution and the washed solution evaporated to give methyl 7- i6acetylxanthene-2-carboxylate.

To a solution of 1.42 g. of methyl 'l-acetylxanthene- Z-carboxylate in120 m1. of acetone and 15 ml. of dimethylformamide are added 3.0 g. ofmagnesium sulfate and 2.5 ml. of 8N chromic acid in 8N sulfuric acid.The resultant mixture is stirred at room temperature for 50 minutesafter which time a solution of4 g. of sodium bisultite in 20 ml. ofwater is added. After this time, 250 ml. of water and 25 ml. of sulfuricacidzwater (1:1) are added. The mixture is stripped of solvent andfiltered. The precipitate is washed with 50 ml. of water to give methyl7-acetylxanthone-Z-carboxylate which is recrystallized from methanol(displacement from methylene chloride solution).

A solution of 2 g. of methyl 7-acetylxanthone-2- carboxylate in 200 ml.of 10 percent aqueous. 10 percent potassium hydroxide in methanol isheated at reflux under a nitrogen atmosphere for 45 minutes. After thistime, 20 ml. of water are added and the resultant mixture heated atreflux for minutes. Water (300 ml.) is then added and the resultantmixture acidified and filtered to give 7-acetylxanthone-Z-carboxylicacid.

EXAMPLE 3 The procedure of Example 2 is repeated employing, in theprocedure of the third paragraph thereof. the acyl chlorides (preparedfrom the corresponding acids upon treatment with thionyl chloride oroxalyl chloride) listed in Column A below to prepare the correspondingacid products listed in Column B below, through their respective methylesters.

Column A Column 8 propionyl chloride n-butyryl chloride isobutyrylchloride n-pentanoyl chloride isopentanoyl chloride sec-pentanoylchloride t-pentanoyl chloride n-hexanoyl chloride n-heptanoyl chloriden-octanoyl chloride n-nonanoyl chloride cyclopropylcarbonyl chloridecyclobutylcarbonyl chloride cyclopentylcarbonyl chloridecyclohexylcarbonyl chloride trifluoro acetyl chloride difluoroacetylchloride trichloroacetyl chloride dichloroacetyl chloride benzoylchloride p-chlorobenzoyl chloride p-methylbenzoyl chloridep-methoxybenzoyl chloride pthiomethoxybenzoyl chloride furoyl chloridepyrroyl chloride thenoyl chloride 7-propionylxanlhone-Z-carboxylic acid7-n-butyrylxanthone-2-carboxylic acid 7-isobutyrylxarithone l-carboxylicacid 7-n-pentanoylxanth0ne-2-carb0xylic acid7-isopentanoylxanthone-Lcarboxylic acid7sec-pentanoylxanthone-Z-carboxylic acid7-t-peritanoylxanthone-Z-carboxylic acid7-n-hexanoylxanthone-Z-carboxylic acid 7-nheptanoylxanthone-2carboxylicacid 'i-moctanoylxanthoneQ-carboxylic acid7mmonanoylxanthone-Z-carboxylic acid 7-cyclopropylcarbonylxanthone-2-carboxylic acid 7 cyclobutylcarbonylxanthone-2- carboxylic acid7-cyclopentylcarbonylxanthone2- carboxylic acid7-cyclohexylcarbonylxanthone-2- carboxylic acid7trifluoroacctylxanth0ne-2carboxylic acid 7'difluoroacctylxanthone 2 carboxylic acid 7-trichloroacetylxanthone-Z-carboxylic acid7-dichloroacctylxanthone-2-car boxylic acid lbcnzoylxunthone-2carboxylicacid 7-(p chlorobenzoyl)xanthone-2-car boxylic acid7-tp-rnethylbenzoyi)xanthone-2carboxylic acid'Hp-methoxybenzoyl)xanthonc-Z- curhoxylic acid'I-tp-thiomcthoxybcnzoyl)xanthone-2- curboxylic acid7furoylxanthone-Z-carboxylic acid 7-pyrroylxanthonc-lcurboxylic acid 7thenoylxanthone2-carboxylic acid The foregoing is practiced using thecorrespondfiig acyl bromide starting compounds, with similar results.

EXAMPLE 4 A mixture of 1.077 g. of methyl 7-acetylxanthone-2-carboxylate, 200 mg. of sodium borohydride and 150 ml. oftetrahydrofuran is stirred for 2.5 hours at room temperature. Thereaction is monitored by tlc. After this period of time, a aqueousacetic acid solution is added to the reaction mixture dropwise toneutrality and the resultant solution evaporated under vacuum andcrystallized by the addition of ethanol and hot water. The precipitateis filtered off, washed and dried to give methyl 7-(l-hydroxyethyl)-xanthone-2- carboxylate.

A mixture of 860 mg. of methyl 7-( l-hydroxyethyl)-xanthone-2-carboxylate, 60 ml. of ethanol and 2 ml. of 2N sodiumhydroxide is refluxed for 30 minutes. The resultant mixture is cooled,acidified and the precipitate is filtered off, washed, and dried to give7-(1- hydroxyethyl )-xanthone-2-carboxylic acid.

The foregoing procedures are practiced upon the other 7-acyl methylesters prepared as described in Example 3 to give the followingproducts, through their respective methyl esters:

7-( 1-hydroxy-n-propyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-butyl )-xanthone-2-carboxylic acid, 7-(l-hydroxyisobutyl )-xanthone-2-carboxylic acid, 7-( l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-is0pentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-sec-pentyl )-xanthone-2-carboxylic acid,

7-( 1-hydroxy-t-pentyl)-xanthone-2-carboxylic acid,

7-( 1-hydroxy-n-hexyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-heptyl )-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid,

7-( 1-hydroxy-n-nonyl)-xanthone-2-carboxylic acid,

7-((cyclopropyl)hydroxymethyl)-xanthone-2- carboxylic acid,

7-((cyclobutyl)hydroxymethyl)-xanthone-2- carboxylic acid,

7-((cyclopentyl)hydroxymethyl)-xanthone-2- carboxylic acid,

7-( cyclohexyl )hydroxymethyl )-xanthone-2- carboxylic acid.

7-( 2,2,2-trifluorol-hydroxyethyl )-xanthone-2- carboxylic acid.

7-(2,2-difluoro-1-hydroxyethyl)-xanthone-2- carboxylic acid,

7-( 2,2,2-trichlorol -hydroxyethyl )-xanthone-2- carboxylic acid,

7-(2,2-dichloro-1-hydroxyethyl)-xanthone-2- carboxylic acid,

7-((phenyDhydroxymethyl)-xanthone-2-carboxylic acid,

7-((p-chlorophenyl)hydroxymethyl)-xanthone-2- carboxylic acid,

7-( (p-methylphenyl )hydroxymethyl )-xanthone-2- carboxylic acid,

7-( (p-me thoxyphenyl )hydroxymethyl )-xanthone-2- carboxylic acid,

7-( (p-thiomethoxy phe nyl )hydroxymethyl xanthoneQ-carboxylic acid,

7-((furyl)hydroxymethyl)xanthone-2-carboxylic acid,

7-( (pyrryl )hydroxymethyl )-xanthone-2-carboxylic acid,

7-( thienyl )hydroxymethyl )-xanthone-2-carboxylic acid,

7-(( pyridyl )hydroxymethyl )-xanthone-2-carboxylic acid,

7-( imidazolyl )hydroxymethyl )-xanthone-2- carboxylic acid,

7-( oxazolyl )hydroxymethyl )-xanthone-2-carboxylic acid.

EXAMPLE 5 A solution of 4.1 g. of methyl 7-acetylxanthone-2- carboxylatein ml. of tetrahydrofuran is stirred at 0C and 6.8 ml. of 3Mmethylmagnesium bromide solution in ether are added dropwise. Afterstirring at 0C for 30 minutes, the reaction mixture is left to warm upto room temperature. A saturated ammonium chloride solution (50 ml.) isthen added and the mixture is concentrated in vacuo. Extraction withethyl acetate followed by evaporation yields methyl 7-(l-hydroxy-lmethylethyl)-xanthone-2-carboxylate. Hydrolysis provides 7-(l-hydroxyl -methylethyl)-xanthone-2- carboxylic acid.

The foregoing procedure is practiced upon the other 7-acyl methyl estersprepared as described in Example 3 to give the following products,through their respective methyl esters:

7-( l-hydroxy- 1 -methyl-n-propyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-butyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-isobutyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-pentyl )-xanthone-2- carboxylic acid,

7-( l-hydroxy- 1 -methyl-isopentyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-sec-pentyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-t-pentyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-hexyl )-xanthone-2- carboxylic acid,

7-( 1-hydroxy-l-methyl-n-heptyl)-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-octyl )-xanthone-2- carboxylic acid,

7-( l-hydroxyl -methyl-n-nonyl )-xanthone-2- carboxylic acid,

Column C Column D cyclobutylmagnesium 7-( l-hydroxyl -cyclobutylethyl)-bromide xanthone-Z-carboxylic acid.

7-( l-hydroxyl c 'clobutyl n-propyl)- xanthone2-carboxylic acid. and soforth,

7-( l-hydroxy-l-cyclopentylethyU- xanthone-2-carboxylic acid.

cyclopentylmagnesium bromide 7-( Lhydroxyl cyclopentyl-n-propylcyclohexylmagnesium bromide EXAMPLE 7 A mixture of methylxanthene-Z-carboxylate (5.1 g.), 7.0 g. of aluminum chloride, 3 g. ofchloroacetyl chloride, and 100 ml. of dichloroethane is stirred at roomtemperature for four hours. After the addition of hy-' drochloricacid-ice followed by chloroform extraction, the mixture is filteredthrough alumina (CH Cl and evaporated to give methyl7-chloroacetylxanthene-2- carboxylate.

The thus-prepared compound is oxidized according to the procedure of thefourth paragraph of Example 2 to give methyl7-chloroacetylxanthone-2-carboxylate.

A mixture of 750 mg. of methyl 7- chloroacetylxanthone-2-carboxylate,200 mg. of sodium borohydride, and 75 ml. of tetrahydrofurari is stirredfor one hour at room temperature. Tlc (CH Cl /AcOEt 9:1) indicates thereaction is complete. Excess sodium borohydride is destroyed by thedropwise addition of aqueous acetic acid (5%). The mixture isconcentrated in vacuo and extracted with ethyl acetate to give methyl7-(l-hydroxy-2- chloroethyl)-xanthone-2-carboxylate.

A mixture of 750 mg. of methyl 7-(l-hydroxy-2-chloroethyl)-xanthone-2-carboxylate, 150 mg. of sodium hydride, 75 ml.of dimethylformamide is stirred for three hours at room temperature.Excess sodium hydride is destroyed by adding a few drops of acetic acid.The mixture is then diluted with water, extracted with ethyl acetate andchromatographed on 75 g. of silica (Cl-l Cl /AcOEt; 9:1) to give methyl7-(l,2- oxidoethyl)-xanthone-2-carboxylate.

A mixture of 118 mg. of methyl 7-(l,2-oxidoethyl)-xanthone-Z-carboxylate, 100 mg. of periodic acid, and ml. oftetrahydrofuran is stirred at room temperature for 2 hours. After thistime, 15 m1. of methylene chloride is added, the mixture filteredthrough alumina (CH Cl and evaporated. The residue is crystallized frommethylene chloridezmethanol to give methyl 7-formylxanthone-Z-carboxylate.

A mixture of 1.2 g. of methyl 7-formylxanthone-2- carboxylate, 10 ml. of2N sodium hydroxide, and 90 ml. of ethanol is refluxed for 60 minutes.Then, it is acidified, cooled, and suction filtered to give7-formylxanthone-2-carboxylic acid.

Reduction thereof as described in the first paragraph of Example 4 gives7-hydroxymethylxanthone-2- carboxylic acid.

Employing methyl 5-chloroacetylxanthene-2- carboxylate, prepared asdescribed above, in the above procedure, affords5-formylxanthone-Z-carboxylic acid which can be reduced to5-hydroxymethylxanthone-2- carboxylic acid.

EXAMPLE 8 5-Ethylxanthone-2-carboxylic acid is prepared from1,3-dicarbomethoxy-4-bromobenzene and oethylphenol in accordance withthe procedures set forth in Example 1 above.

A mixture of 4 g. of the thus-obtained 5-ethylxanthone-2-carboxylicacid, 10 g. of methyl iodide, and 10 g. of potasium carbonate in 50 ml.of dimethylformamide is stirred at room temperature for a period of 16hours. After this period of time, the reaction mixture is poured intodilute hydrochloric acid-ice and the resultant mixture extracted withethyl acetate.

The extracts are filtered through alumina to give methyl5-ethylxanthone-2-carboxylate which can be recrystallized from methanol.

A suspension of 2.5 g. of methyl 5-ethylxanthone-2- carboxylate and 2.5g. of chromic oxide in 190 ml. of acetic acid and 10 ml. of aceticanhydride is stirred at room temperature for a period of 6 hours. Aftermonitoring the reaction by tlc indicates the absence of startingmaterial, 10 ml. of isopropanol are added and the resultant mixturewarmed on the steam bath. Water (200 ml.) is then added portionwise tothe resultant mixture is cooled to room temperature. The precipitate isfiltered off, washed, and dried to obtain methyl 5-acetylxanthone-2-carboxylate.

A mixture of 1.09 g. of methyl 5-acetylxanthone-2- carboxylate, ml. ofisopropanol, 5 ml. of saturated sodium carbonate solution, and 25 ml. ofwater is re fluxed for two hours. The resultant mixture is thenacidified, cooled and the crystals filtered off, washed, and dried togive 5-acetylxanthone-2-carboxylic acid.

The foregoing procedures can be followed with other 5-substituted methylcompounds (prepared according to the procedures of Example 1) to givethe corresponding 5-acyl compounds, to wit:

5-propionylxanthone-2-carboxylic acid;

5-n-butyrylxanthone-2-carboxylic acid; 5-isobutyrylxanthone-2-carboxylicacid; 5-n-pentanoylxanthone-2-carboxylic acid;5-isopentanoylxanthone-2-carboxylic acid;

S-sec-pentanoylxanthone-Z-carboxylic acid;

5-t-pentanoylxanthone-2-carboxylic acid;

5-n-hexanoylxanthone-Z-carboxylic acid;5-n-heptanoylxanthone-2-carboxylic acid;5-n-octanoylxanthone-2-carboxylic acid;

S-n-nonanoylxanthone-2-carboxylic acid;

-cyclopropylcarbonylxanthone-Z-carboxylic acid;5-cyclobutylcarbonylxanthone-2-carboxylic acid;5-cyclopentylcarbonylxanthone-2-carboxylic acid;5-cyclohexylcarbonylxanthone-Z-carboxylic acid;5-trifluoroacetylxanthone-Z-carboxylic acid;5-difluoroacetylxanthone-Z-carboxylic acid;5-trichloroacetylxanthone-2-carboxylic acid;5-dichloroacetylxanthone-2-carboxylic acid;S-benzoylxanthone-2-carboxylic acid; S-( p-chlorobenzoyl)-xanthone-2-carboxylic acid; 5 p-methylbenzoyl )-xanthone-2-carboxylicacid; 5-(p-methoxybenzoyl)-xanthone-2-carboxylic acid; 5-(p-thiomethoxybenzoyl )-xanthone-2-carboxylic acid;5-furoylxanthone-Z-carboxylic acid: 5-pyrroylxanthone-2-carboxylic acid;S-thenoylxanthone-2-carboxylic acid;5-pyridylcarbonylxanthone-2-carboxylic acid;5-imidazolylcarbonylxanthone-Z-carboxylic acid;S-oxa2olylcarbonylxanthone-2-carboxylic acid.

EXAMPLE 9 Methyl 5-acetylxanthone-2-carboxylate is treated in accordancewith the procedure of the first paragraph of Example 4, to give methyl5-( l-hydroxyethyl)- xanthone-Z-carboxylate which is hydrolyzed inaccordance with the second paragraph thereof to give 5-(1-hydroxyethyl)-xanthone-2-carboxylic acid.

The foregoing procedures can be followed with other S-acyl methyl estersprepared as described in Example 8 to give the corresponding5-(l-hydroxyalkyl) compounds through their methyl esters, to wit:

5-( l-hydroxy-n-propyl )-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-butyl xanthone-2-carboxylic acid; 5-( l-hydroxyisobutyl)-xanthone-2-carboxylic acid; 5-(l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid;

5-( l-hydroxyisopentyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-sec-pentyl-xanthone-2-carboxylic acid;

5-( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-hexyl )-xanthone-2-carboxylic acid;

5-hydroxy-n-heptyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-nonyl )-xanthone-2-carboxylic acid;

5-((cyclopropyl)hydroxymethyl)-xanthone-2- carboxylic acid;

5-((cyclobutyl)hydroxymethyl)-xanthone-2- carboxylic acid;

5-((cyc1opentyl )hydroxymethyl)-xanthone-2- carboxylic acid;

I 5 ((cyclohexyl)hydroxymethyl)-xanthone-2- carboxylic acid;

5-( 2,2,2-trifluorol -hydroxyethyl)-xanthone-2- carboxylic acid;

5-(2,2-difluoro-1-hydroxyethyl)-xanthone-2- carboxylic acid;

5-(2,2,2-trichloro-l-hydroxyethyl)-xanthone-2- carboxylic acid;

5-( 2,2-dichlorol -hydroxyethyl )-xanthone-2- carboxylic acid;

5-((phenyl)hydroxymethyl)-xanthone-2-carboxylic acid 5-( (p-chlorophenyl)hydroxymethyl )-xanthone-2- carboxylic acid;

5-( (p-methylphenyl )hydroxymethyl l-xanthone-l carboxylic acid;

5-((p-methoxyphenyl )hydroxymethyl l-xamhonelcarboxylic acid;

5-( (p-thiornethoxyphenyl )hyd roxymethyl xanthone-Z-carboxylic acid;

5-( furyl )hydroxymethyl )-xanthone-2-carboxylic acid;

5-( (pyrryl )hydroxymethyl )-xanthone-2-carboxylic acid;

5 (thienyl )hydroxymethyl )-xanthone-2-carboxylic acid;

5-((pyridyl )hydroxymethyl )-xanthone-2-carboxyl ic acid;

5-( (imidazolyl )hydroxymethyl )-xanthone-2- carboxylic acid;

5-( (oxazolyl )hydroxymethyl )-xanthone-2-carboxylic acid.

EXAMPLE lO Methyl S-acetylxanthone-Z-carboxylic acid is treated inaccordance with the procedure of the first paragraph of Example 5 togive methyl 5( l-hydroxyl methylethyl)-xanthone-2-carboxylate which ishydrolyzed in accordance with the second paragraph thereof to give 5-(l-hydroxyl -methylethyl )-xanthone-2- carboxylic acid.

The foregoing procedure is practiced upon the other S-acyl methyl estersprepared as described in Example 8 to give the following products,through their respective methyl esters:

5-( l-hydroxyl-methyl-n-propyl )-xanthone-2- carboxylic acid;

5( l-hydroxyl -methyl-n-butyi )-xanthone-2- carboxylic acid; 5-(l-hydroxyl -methyl-isobutyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl -methyl-n-pentyl )-xanthone-2- carboxylic acid;

5-( l-hydroxy l -methyl-isopentyl)-xanthone-2- carboxylic acid;

5-( l-hydroxy-l-methylsec-pentyl)-xanthone-2- carboxylic acid;

5-( l-hydroxy-l-methy-t-pentyl)-xanthone-2- carboxylic acid;

5-( Lhydroxyl -methyl-n-hexyl )-xanthone-2- carboxylic acid;

5-( l-hydroxyl -methyl-n-heptyl)-xanthone-2- carboxylic acid;

5-( 1 -hydroxyl -methyl-n-octyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl -rnethyl-n-nonyl )-xanthone-2- carboxylic acid;

5-( l-hydroxyl -cyclopropylethyl)-xanthone-2- carboxylic acid;

5-( l-hydroxyl-cyclobutylethyl )-xanthone-2- carboxylic acid;

S-( l-hydroxyl -cyclopentylethyl )-xanthone-2- carboxylic acid;

5-( 1 hydroxy-] -cyclohexylethyl )-x anthonc-Z carboxylic acid;

5( l -hydroxyl -trilluoromcthylcthyl )-xanthonc-2 carboxylic acid;

5-( l-hydroxyl -difluoromethylethyl )xanthonc-2- carboxylic acid;

xanthone-Z-carboxylic acid. and so forth.

-( l-hydroxyl-cyclophexylethyl xanthone-2-carboxy1ic acid 5-( lhydroxy-1 -cyclohexyl-n-propyl xanthone-2-carboxylic acid. and so forth.

cyclohcxylmagnesium bromide EXAMPLE 12 Methyl5-methylxanthone-2-carboxy1ate is prepared by the procedure of Example 1from o-methylphenol, followed by the preparation of the methyl ester ofthe thus-produced acid.

To a solution of 2.4 g. of methyl 5-methylxanthone-2- carboxylate in 30ml. acetic acid and 30 ml. acetic an-- hydride are added 4.8 ml.concentrate sulfuric acid at 0C. After the addition of 5.6 g. of chromicacid, the mixture is stirred for five hours. The crude diacetoxymethylintermediate is isolated by diluting the reaction mixture with water andfiltering off the precipitate. The formyl derivative is obtained byrefluxing the diacetoxymethyl compound thus obtained with ml. 2Nsulfuric acid in 90 ml. methanol for 30 minutes, cooling, diluting with60 ml. water and filtering off the precipitate to give5-formy1xanthone-Z-carboxylic acid. This compound can be reduced asdescribed above to 5-hydroxymethylxanthone-Z-carboxylic acid.

7-Formylxanthone-Z-carboxylic acid is prepared by the above procedure,preferably by using 30 ml. of 2N sulfuric acid in 70 ml. of ethanol for2 hour treatment of the diacetate.

EXAMPLE 1 3 A mixture of 51.5 g. of 1,3-dimethyl-4-iodobenzene(4-iodo-m-xylene), 40 g. of o-formylphenol, 16 g. of cuprous oxide in300 ml. of dimethylacetamide is heated to the boiling point andmaintained under reflux (190C) for 144 hours with stirring and under anitrogen atmosphere. The reaction mixture is then poured into ice waterand extracted with ether and the extracts are filtered through 500 g. ofalumina in hexane to give 1 ,3-dimethyl-4-o-formylphenyloxy)-benzene.

A mixture of 41 g. of 1,3-dimethyl-4-(o-formylphenyloxy)- benzene, 300g. of potassium permanganate, 500 ml. of t-butanol, and 750 ml. of wateris, heated to the boiling point and maintained thereat for a period ofthree hours. After distilling off the tbutanol, the reaction mixture isfiltered, the clear filtrate acidified and the precipitate of1,3-dicarboxy-4- (o-formylphcnyloxy)-benzene is isolated by suctionfiltration and washed with water.

The l ,3-dicarboxy-4-( o-formylphenyloxy J benzene thus prepared is thencyclized as described in Examples 1 or 14 to give5-formylxanthone-2-carboxylic acid.

In like manner, the other OS and -7-substituted xanthone-Z-carboxylicacid compounds hereof are prepared. These compounds can then be treatedas described in Examples 4 to 6 and 8 to 11 to prepare the correspondingC-5 and -7-substituted compounds.

EXAMPLE 14 A mixture of 2.84 ml. of o-ethylphenol, 5.0 g. of 1,3-dicarbomethoxy-4-bromobenzene and 1.31 g. of cuprous oxide in ml. ofdimethylacetamide is stirred under reflux overnight. The resultantmixture is then poured on ice and extracted with ether. The etherextracts are washed with water and 2N aqueous sodium hydroxide. Thewashed extracts are dried and evaporated to give1,3-dicarbomethoxy-4(o-ethylphenyloxy)-benzene which can be purified bychromatography through alumina with gradient elution with benzene:-hexane (50:50 60:40).

A mixture of 24 g. of 1,2-dicarbomethoxy-4-(o-ethylphenyloxyl)-benzene,20 g. of potassium hydroxide, 300 ml. of ethanol and 20 ml. of water areheated on a steam bath for about one-half hour. After this time, thereaction mixture is acidified with dilute hydrochloric acid and theethanol evaporated. The resultant mixture is then extracted with ethylacetate and the ex tracts are dried and evaporated to give1,3-dicarhoxy- 4-(o-ethylphenyloxy)-benzene which can be crystallizedfrom methanolzethyl acetate.

A mixture of 1.94 g of l,3-dicarboxy-4-(o-ethylphenyloxy)-benzene, 40ml. of sulfolane and 30 ml. of polyphosphoric acid is stirred at C for30 minutes. The resultant mixture is then diluted with water and thediluted mixture filtered. The precipitate is washed neutral, and thendissolved and heated in ethanol containing charcoal. The resultantmixture is then filtered, and the ethanol is partially evaporated. Wateris added until crystallization starts. Filtration gives the solidproduct 5-ethylxanthone-Z-carboxylic acid which can be recrystallizedfrom ethanol.

The foregoing product is useful as described in Example 8 et seq.

In like manner, the foregoing reactions can be conducted using analternate 1,3-dicarboalkoxy-4- halobenzene starting material such as1,3-dicarboxy-4- bromobenzene, 1,3-dicarboethoxy-4 iodobenzene, and soforth, with similar results.

Upon substituting the other phenol starting compounds in the process ofthe preceding example, there are obtained the corresponding C-5 and C-7substituted xanthone-Z-carboxylic acids.

EXAMPLE 15 To a solution of 6 g. of methyl 7acetylxanthene-2-carboxylate in 500 ml. of absolute methanol are added 1.1 g. of sodiumborohydride in 50 m1. of water at a temperature of from 25 to 30C withstirring. over a period of about 30 minutes. After 15 minutes underthese conditions, 400 ml. of water and 20 ml. of acetic acid are addedand the resultant mixture is stripped of solvent. The resultant mixtureis extracted with methylene chloride and washed with bicarbonate andwater. The washed extracts are concentrated to give methyl 7-(l-hydroxy-ethyl )-xanthene-Z-carboxylate.

A solution of 5.5 g. of methyl 7-(l-hydroxyethyl)-xanthene-2-carboxylate in 100 ml. of pyridine is cooled in an ice bath.To the cooled solution are added 2.91 ml. of acetyl chloride and theresultant mixture is stirred in an ice bath for one-half hour and thenat room temperature for 1 hour. After this time, the reaction mixture ispoured into dilute hydrochloric acid-ice and the precipitate is filteredoff and washed to give methyl 7-(I-acetoxyethyl)-xanthene-2-carboxylate.

To a solution of 3 g. of methyl 7-(l-acetoxyethy1)-xanthene-2-carboxylate in 80 ml. of acetone are added 12 ml. of 8Nchromic acid in 8N sulfuric acid. The resultant mixture is stirred atroom temperature for 1% hours. Excess chromic oxide is decomposed withaqueous sodium bisulfite and to the resultant mixture are added 500 ml.of water. The resultant mixture is stripped of solvent and extractedwith methylene chloride. The methylene chloride extracts are washed with10 percent aqueous sodium bicarbonate solution and the washed extractsare concentrated in vacuum to give methyl 7-(1-acetoxyethyl)-xanthone-2-carboxylate.

A solution of 2.70 g. of methyl 7-(l-acetoxyethyl)-xanthone-Z-carboxylate in 300 ml. of a 10% potassium hydroxide 10percent aqueous methanol solution is heated under reflux under anitrogen atmosphere for a period of one hour. After this time, 40 ml. ofconcentrated hydrochloric acid in 70 ml. of water are added. Thereafter,lOO ml. of water are added and the resultant solution is stripped ofsolvent in vacuum and filtered to give 7-( l-hydroxyethyl)-xanthone-2-carboxylic acid.

In like manner, by subjecting the other 7-acyl or 5- acylxanthone-Z-carboxylic compounds as described in Examples 1 to 3 and 8above to the procedure of the present example, the corresponding(l-hydroxyalkyl)- xanthone-Z-carboxylic acid compounds are prepared.

EXAMPLE 16 A mixture of 2 g. of 7-( l-hydroxyethyl)-xanthone-2-carboxylic acid in 8 ml. of pyridine and 4 ml. of acetyl chloride isheated at steam bath temperatures for one hour. The mixture is thenpoured into HCl/ice water and the solid which forms is collectd byfiltration, washed with water and dried to yield 7-(1-acetoxyethyl)-xanthone-2-carboxylic acid.

In a similar manner, 5-( l-acetoxyethyl)-xanthone-2- carboxylic acid isprepared.

Upon substitution of the appropriate acyl chloride in the aboveprocedure and, in addition, employing as starting compounds the productslisted in Examples 4 and 9, the following compounds are prepared:

7-( 1-propionyloxyethyl)-xanthone-2-carboxylic acid,

5-( l-propionyloxyethyl )-xanthone-2-carboxylic acid,

7-( l-butyryloxyethyl)-xanthone-2-carboxylic acid,

5-( l-butyryloxyethyl)-xanthone-2-carboxylic acid,

7-( 1-acetoxy-n-propyl)-xanthone-2-carboxylic acid,

5-( l-acetoxy-n-propyl)-xanthone-2-carboxylic acid,

and so forth.

7-( l-acetoxy-nbutyl)-xanthone-2-carboxylic acid,

5-( l-acetoxy-n-butyl)-xanthone-2-carboxylic acid,

and so forth.

7-( l-acetoxyisobutyl)-xanthone-2-carboxylic acid,

5-( l-acetoxyisobutyl)-xanthone-2-carboxylic acid,

and so forth,

7-( (cyclopropyl)acetoxymethyl)-xanthone-2- carboxylic acid,

30 5-((cyclopropyl)acetoxymethyl)-xanthone-2- carboxylic acid, and soforth, 7-( (phenyl)acetoxymethyl )-xanthone-2-carboxylic acid,5-((phenyl)acetoxymethyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 17 A mixture of 2 g. of 7-(l-hydroxy-l-methylethyl)-xanthone-Z-carboxylic acid, 15 ml. of tetrahydrofuran, 5 ml. ofdimethylaniline, and 5 ml. of acetyl chloride is refluxed for six hours.The mixture is then concentrated in vacuo to remove a portion of thetetrahydrofuran. Dilute HCl is added, the mixture. is filtered, washedand dried to give 7-( l-acetoxy-1-methylethyl)- xanthone-Z-carboxylicacid.

In a similar manner, 5-( l-acetoxy-l-methylethyl)- xanthone-Z-carboxylicacid is prepared.

Upon substitution of the appropriate acyl chloride in the aboveprocedure and, in addition, employing as starting compounds the productslisted in Examples 5, 6, l0 and ll, the following compounds areprepared:

7-( l-acetoxy- 1 -methyl-n-propyl)-xanthone-2- carboxylic acid,

7-( l-acetoxyl -methyl-isobutyl )-xanthone-2- carboxylic acid,

7-( l-propionyloxyl -methyl-n-propyl)-xanthone-2- carboxylic acid,

7-( l-propionyloxyl -methyl-isobutyl )-xanthone-2- carboxylic acid,

7-( l-acetoxyl -ethylethyl )xanthone-2-carboxylic acid,

7-( l-acetoxy-1-isopropylethyl)-xanthone-2- carboxylic acid,

5-( l-acetoxy- 1 -methyl-n-propyl)-xanthone-2- carboxylic acid,

5-( 1-acetoxy-l-methyl-isobutyl)-xanthone-2- carboxylic acid,

5 l-propionyloxy- 1 -me thyl-n-propyl )-xanthone-2- carboxylic acid,

5-( l-propionyloxy- 1 -methyl-isobutyl)-xanthone-2- carboxylic acid,

5-( l-acetoxy-1-ethylethyl)-xanthone-2-carboxylic acid, and

5-( l-acetoxyl -isopropylethyl )-xanthone-2- carboxylic acid.

EXAMPLE18 To a mixture of 2.5 g. of methyl 7-( l-hydroxyethyl)-xanthone-2-carboxylate and 500 mg. of sodium hydride in 45 ml. ofdimethylformamide is added 2 ml. of methyl iodide and the mixture isstirred at room temperature for 16 hours. The mixture is then pouredinto dilute I-lCl/ice water, filtered and dried to give methyl 7-(1-methoxyethyl)-xanthone-2-carboxylate.

The resultant product is hydrolyzed according to the procedure ofParagraph 2 of Example 1 to give 7-(1-methoxyethyl)-xanthone-2-carboxylic acid.

In a similar manner, 5-( l-methoxyethyl)-xanthone-2- carboxylic acid isprepared.

Upon substitution of the appropriate alkyl or cycloalkyl iodide orbromide and, in addition, employing as starting compounds the productslisted in Examples 4 and 9, the following compounds are prepared,through their respective esters:

7-( l-ethoxyethyl )-xanthone-2-carboxylic acid,

-( l-ethoxyethyi)-xanthone-2-carboxylic acid,

7-( l-n-propoxyethyl)-xanthone-2-carboxylie acid,

5-( l-n-propoxyethyl)xanthone-2 -carboxylic acid,

7-( l-isopropoxyethyl )-xanthone-2-carboxylic acid,

5-( 1-isopropoxyethyl)-xanthone-2-earboxylic acid,

7-( 1-cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

5-( 1cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

7-( 1-methoxy-n-propyl)-xanthone-2-carboxylic acid,

5-( l-methoxy-n-propyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-methoxy-n-butyl)-xanthone-2-earboxylic acid,

5'( l-methoxy-n-butyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-methoxyisobutyl )-xanthone-2-carboxylie acid,

5-( 1-methoxyisobutyl)-xanthone-2-carboxylic acid,

and so forth,

i 7-( eyclopropyl )methoxymethyl )-xanthone-2- earboxylic acid,

5 cyclopropyl)methoxymethyl )-xanthone-2- carboxylic acid, and so forth,

7-( phenyl )methoxymethyl )-xanthone-2-earboxylic acid,

5-( phenyl )methoxymethyl )-xanthone-2-carboxylic acid, and

7-( l-methoxyl -methylethyl )-xanthone-2-earboxylic acid,

5-( l-methoxyl -methylethyl )-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 19 A solution of 4.1 g. of methyl 7-acetylxanthone-2-carboxylate in 120 ml. of tetrahydrofuran is stirred at 0C and 6.8 ml.of 3M methylmagnesium bromide solution in ether are added dropwise.After stirring at 0C for minutes, 2 ml. of methyl iodide and 30 ml. ofhexamethylphosphoramide are added and the mixture is stirred at roomtemperature for five hours. A saturated ammonium chloride solution ml.)is then added and the mixture is coneentratedin vacuo. Extraction withethyl acetate followed by evaporation yields methyl7-(l-methoxy-1-methylethyl)-xanthone-2- earboxylate. Hydrolysis provides7-(l-methoxy-1- methylethyl)-xanthone-2-carboxytic acid.

Likewise 5 1 -methoxy- 1 -methylethyl )-xanthone-2- carboxylic acid isprepared.

Upon substituting the appropriate alkyl or cycloalkyl bromide and, inaddition, using the other starting materials listed in Examples 3 and 8,the following compounds are prepared:

7-( l-ethoxyl-methylethyl )-xanthone-2-earboxylic acid,

5-( l -ethoxyl-methylcthyl )-xanthone-2-carboxylie acid,

7-( l-propoxy-l-methylethyl )-xanthone-2-carboxylic acid,

5-( l-propoxy-l -methylethyl)-xanthone-2-earboxylic acid,

7-( l-cyelopentyloxyl -methylethyl)-xanthone-2- carboxylic acid,

5-( 1 -cyclopentyloxy- 1-methylethyl)-xanthone-2- earboxylic acid,

7-( l -methoxyl -methyl-n-propyl )-xanthone-2- earboxylic acid,

5-( l-methoxyl -methyl-n-propyl )-xanthone-2- earboxylic acid, and soforth,

7-' l-methoxy-1-methyl-isobutyl)-xanthone-2- carboxylic acid,

5-( l-methoxyl -methyl-isobutyl )-xanthone-2- carboxylic acid, and soforth,

7-( l-methoxy-l -cyclopentylethyl )-xanthone-2- carboxylic acid,

5-( l-methoxyl -cyclopentylethyl )-xanthone-2- carboxylic acid, and soforth,

7-( l -methoxyl -phenylethyl )-xanthone2-carboxylic acid,

5-( l-methoxyl -phenylethyl )-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 20 A mixture of 1.6 g. of methyl 7-(l-hydroxyethyl)-xanthone-2carboxylate, 50 mlv of methylene chloride, 50 ml. of isobuteneand 2 ml. of BF /H PO catalyst are shaken in a pressure bottle for fourdays at room temperature. The reaction mixture is diluted with methylenechioride, washed with bicarbonate solution, then water, dried andevaporated and crystallized from methanol to give methyl 7-(lt-butoxyethyl)-xanthone- Z-carboxylate.

Hydrolysis provides 7-( l-t-butoxyethyl)-xanthone-2- earboxylic acid.

Likewise, 5-( l-t-butoxyethyl )-xanthone-2-earb0xylic acid is prepared.

Likewise, the following products are prepared from the respectivestarting compounds:

7-( l-t-butoxy-n-propyl)-xanthone-2-earboxylie acid,

5-( l-t-butoxy-n-propyl )-xanthone-2-earb0xylic acid,

7-( l-t-butoxy-isobutyl)-xanthone-2-carboxylic acid,

5-( l-t-butoxy-isobutyl)-xanthone-2-carboxylic acid,

7-( (cyclopropyl )-t-butoxymethyl )-xanthone'2- carboxylic acid,

5-((cyclopropyl)-t-butoxymethyl)-xanthone-2- carboxylic acid,

7-((phenyl)t-butoxymethyl)-xanthone-2-earboxylic acid,

5-((phenyl)-t-butoxymethyl)-xanthone-2-carboxylic acid,

7-( l-t-butoxyl -methylethyl)-xanthone-2-carboxylie acid,

5-( l-t-butoxy- 1-methylethyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 21 Ten milliliters of dihydropyran are added to a solution of lg. of methyl 7-(l-hydroxyethyl)-xanthone-2- carboxylate in 50 ml. ofbenzene. About l ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is crystallized from chloroform/methanol/pyridine to yield methyl 7-( l-tetrahydropyranl yloxyethyl)-xanthone-2-carboxylate.

Methyl 7-( l-tetrahydropyran-Z '-yloxy-1-methylethyl)-xanthone-2-carboxylate is prepared from methyl 7-(l-hydroxy l -methylethyl )-xanthone-2- carboxylate by conducting theabove reaction at reflux for 2 hours.

Hydrolysis provides 7-( l-tetrahydropyran-2yloxyethyl)-xanthone-2-carboxylic acid and 7-(1- 33 tetrahydropyran-Z'-yloxy- 1 -methylethyl )-xanthone-2- carboxylic acid, respectively.

In like manner. l-tetrahydropyran-2'-yloxyethyl)- xanthoneQ-carboxylicacid is prepared. By use of dihydrofuran in the above procedure, 7-(1-tetrahydrofuran-Z'-yloxyethyl)-xanthone-2-carboxylic acid, 7-(l-tetrahydrofuran-2 '-yloxyl -methylethyl xanthone-Z-carboxylic acid,5-( l-tetrahydrofuran-2'- yloxyethyl)-xanthone-2-carboxylic acid, 5-(ltetrahydrofuran-2 '-yloxyl -methylethyl )xanthone-2- carboxylic acidare prepared.

In like manner, the following compounds are prepared:

7-( l-tetrahydropyran-2 -yloxy-n-propyl )-xanthone- 2-carboxylic acid,

7-( l-tetrahydropyran-2'-yloxy-isobutyl)-xanthone-2- carboxylic acid,

7-( l-te trahydropyran-2 '-yloxyl -ethylethyl xanthone-2-carboxylicacid, and the tetrahydrofuran-2-yloxy and C-5 substituted compoundscorresponding thereto.

3.5 grams of methyl 7-( l-hydroxyethyl)-xanthone-2- carboxylate in l50ml. of benzene and 500 mg. of p-toluene-sulfonic acid (dried byazeotropic distillation from benzene) are mixed together and thereaction mixture is treated with 4-methoxy-5,6-dihydro-2H- pyran, 1 ml.at a time until reaction is complete (followed by tlc). The reaction isquenched by addition of 1/2 ml. of triethylamine, washed with water, andcrystallized with care from methanol containing pyridine to give methyl7-( l-4-methoxytetrahydropyran-4'- yloxyethyl))-xanthone-2-carboxylate.

Methyl 7-( l-4 '-methoxytetrahydropyran-4'-yloxylmethyl-ethyl)-xanthone-2-carboxylate is prepared from methyl 7-(l-hydroxyl -methylethyl)-xanthone-2- carboxylate by conducting the abovereaction at reflux for 2 hours.

Hydrolysis provides 7-( l-4'-methoxytetrahydropyran-4'-yloxyethyl)-xa.nthone-2- carboxylic acid and7-( l-4'-methoxy-tetrahydropyran- 4'-yloxyl-methylethyl)-xanthone-2-carboxylic acid respectively.

A solution of 1.4 g. of aluminum chloride in 25 ml. of tetrahydrofuranis treated with a solution of 0.4 g of lithium aluminum hydride in 100ml. of ether. Methyl 7-( l-4'-methoxy-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylate (500 mg.) is extracted into the solution. Afterreduction is complete (monitored by tlc). saturated sodium chloride isadded until a precipitate forms. This is filtered and the crude productis oxidized in acetic acid using excess sodium dichromate to give 7-(l-tetrahydropyran-4-yloxyethyl)-xanthone-2- carboxylic acid.

In like manner, the following compounds are prepared:

5-( l-4'-methoxytetrahydropyran-4'-yloxyethyl xanthone-Z-carboxylicacid,

5-( l-tetrahydropyran-4 -yloxyethyl )-xanthone-2- carboxylic acid,

7 l-4'-ethoxytetrahydropyran-4'-yloxyethyl)- xanthone-Z-carboxylic acid,

5-( l-4-ethoxytetrahydropyran-4'-yloxyethyl)- xanthone-Z-carboxylicacid,

7-( l-4'-methoxytetrahydropyran-4'-yloxyisobutyl)- xanthone-Z-carboxylicacid,

5-( l-4'-methoxytetrahydropyran-4'-yloxyisobutyl)- xanthone-Z-carboxylicacid,

7-( l-tetrahydropyran-4-yloxyl -methylethyl)- xanthone-2-carboxylicacid,

34 5 1-tetrahydropyran-4-yloxylmethylethyl xanthone-Z-carboxylic acid,7-( l-4'-propoxytetrahydropyran-4 '-yloxy-n-propyl)-xanthone-Z-carboxylic acid, and 5-(l-4-propoxytetrahydropyran-4'-yloxy-n-propyl xanthone-2-carboxylic acid.

EXAMPLE 22 A mixture of 4.5 g. of 7-acetylxanthone-2-carboxylic acid, 10g. of methyl iodide, and 10 g. of lithium carbonate in ml. ofdimethylformamide is stirred at room temerpature for a period of 18hours. After this period of time, the reaction mixture is poured intodilute hydrochloric acid-ice and the resultant precipitate is filteredoff and washed to give methyl 7- acetylxanthone-2-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyliodides so as to prepare the corresponding lower alkyl acid estershereof, e.g., ethyl 7- acetylxanthone-2-carboxylate, n-propyl 7-acetylxanthone-2-carboxylate isopropyl 7- acetylxanthone-2-carboxylate,n-propyl 7- acetylxanthone- 2-carboxylate isobutyl 7-acetylxanthone-2-carboxylate, sec-butyl 7- acetylxanthone-2-carboxylate,t-butyl 7- acetylxanthone-Z-carboxylate n-pentyl 7-acetylxanthone-2-carboxylate, and so forth.

In like manner, the other xanthone-2-carboxylic acids thereof containingsubstitutents at the C-5 or C-7 positions, prepared as described above,can be converted to the corresponding acid esters.

EXAMPLE 23 To a solution of 10 g. of 7-acetylxanthone-2- carboxylic acidin 200 ml. of ethanol is added the theoretical amount of sodiumhydroxide dissolved in 200 ml. of percent ethanol. The reaction mixtureis then concentrated in vacuum to give sodium 7-acetylxanthone-2-carboxylate.

Sodium 7-( l-hydroxyethyl )-xanthone-2-carboxylate and sodium5-acetylxanthone-2-carboxylate are also thus prepared.

In a similar manner, the potassium and lithium salts are prepared.Similarly, by replacing the sodium salt by means of an appropriate metalsalt reagent, e.g., calcium chloride, manganese chloride, and so forth,the other xanthone-Z-carboxylic acid salts are prepared, e.g., magnesium7-acetyl-xanthone-Z-carboxylate, calcium 7-acetylxanthone-Z-carboxylate,aluminum 7- acetylxanthone-Z-carboxylate, ferrous7-acetylxanthone-2-carboxylate, zinc 7-acetylxanthone-2- carboxylate,manganese 7-acetylxanthone-2- carboxylate, ferric7-acetyl-xanthone-2-carboxylate, and so forth.

In a similar manner, the xanthone-Z-carboxylic acid salts of the otherC-S or C-7 substituted xanthone-2 carboxylic acids hereof are prepared.

EXAMPLE 24 To a mixture of 50 ml. of concentrated aqueous ammonia in 500ml. of methanol there are added 20 g. of 5-acetylxanthoneZ-carboxylicacid. The resultant mixture is stirred for two hours and is thenevaporated to dryness to give the ammonium salt of5-acetylxanthone-Z-carboxylic acid.

A solution of 10 g. of xanthone-2-carboxylic acid in 50 ml. of thionylchloride is heated at reflux for l hour. Thereafter, the solution isevaporated to dryness to give the corresponding acid chloride to whichis added a concentrated ethereal ammonia solution. The resultantsolution is evaporated giving the ammonium salt of xanthone-Z-carboxylicacid.

In like manner, the lower alkyl amides can be prepared usingmonoalkylamine or dialkylamine in lieu of ammonia in the aboveprocedures. Thus prepared, e. g.,

are

7-propionylxanthone-2-carboxylic acid amide,

N-methyl 7-isobutylrylxanthone-2-carboxylic acid amide,

N,N-dimethyl l-hydroxyethyl)-xanthone-2- carboxylic acid amide,

N,N-diethyl 7-( l-hydroxy- 1 -methyl )-xanthone-2- carboxylic acidamide,

N-ethyl 7-benzoylxanthone-2-carboxylic acid amide,

N-n-propyl 7-furylxanthone-Z-carboxylic acid amide,

and so forth.

EXAMPLE 25 To a mixture of 20 g. of procaine and 500 ml. of

aqueous methanol are added 20 g. of -carboxylic 7-isobutyrylxanthone-Zcarboxylic acid. The resultant mixture is stirred atroom temperature for 16 hours. It.

is then evaporated under reduced pressure to give the procaine salt of7-isobutyrylxanthone-2-carboxylic acid.

Similarly, the lysine, caffeine, and arginine salts thereof areobtained. In like manner, the e.g., procaine, lysine, caffeine, andarginine salts of the other 5- and 7-substituted xanthone-2-carboxylicacids are obtained, e.g., the procaine salt of 7-acetylxanthone-2-carboxylic acid, the caffeine salt ofS-(l-hydroxy-npropyl)xanthone-Z-carboxylic acid, the lysine salt of7-hydroxymethylxanthone-Z-carboxylic acid, the procaine salt of5-hydroxymethylxanthone-2-carboxylic acid, and the arginine salt ofS-acetylxanthone-Z- carboxylic acid.

EXAMPLE 26 The following procedures illustrate the method by which thepharmaceutical compositions of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in 80 ml. of a (9.47 g./l. water)sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00g./l. water) solution (20 ml.) is then added thereto. The resultantsolution having a pH of 7.38 is sterilized in an autoclave. This vehicleis then added to solid, dry xanthone-2 carboxylic acid to give apreparation suitable for intravenous injection containing 2.5 mg. ofxanthone-Z- carboxylic acid per ml. of total composition.

EXAMPLE 27 The following procedure illustrates a test procedure for thecompounds hereof.

Normal female (Sprague-Dawley) rats of 150 to 200 grams each arepassively sensitized intradermally by in jection of rat anti-egg albuminreaginic sera. After 24 hours, each rat is challenged intravenously with1.75 ml. of 0.4 percent Evans blue, 1 mg. egg albumin plus l0.0 mg. ofxanthone-Z-carboxylic acid. Control rats receive noxanthone-Z-carboxylic acid. The dermal bluing is recorded to 25 minuteslater. The rats which receive the xanthone-Z-carboxylic acid exhibit aIOO-percent inhibition of allergic reaction whereas the control ratsexhibit no inhibition.

The above procedure is repeated using 7-acetylxanthone-2-carboxylicacid, with similar results. The above procedure is repeated using oraladministration, with similar results.

Xanthone-Z-carboxylic acid compounds are administered by gavage at adose of 20 mg. per animal l5 minutes prior to challenge. Twenty to 30minutes after challenge the degree of dermal bluing is read, withsimilar results.

Inhibition of reaginic antigen-antibody reactions in rats is regarded asrepresentative of inhibition of human reaginic antigen-antibodyreactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent ofprovoked degree of asthma condition by changes in airway resistance onexpiration. The subject compounds are administered as an aerosol byinhalation before antigen challenge. Prevention of asthmatic conditionsupon the administration of the compounds is evidence by a decrease inairway resis' tance and other subjective improvements, e. g., reducedcough.

What is claimed is:

l. A compound selected from those represented by the following formulas:

00011 R- AAZOOH (lo/0 and the pharmaceutically acceptable, non-toxicalkyl or glycerol esters, unsubstituted, monoalkyl, dialkyl,dialkylaminoalkyl, alkoxyalkyl, or phenethyl substituted amides andsalts thereof; wherein each R is a group of the formula:

in which R is hydrogen; lower alkyl; cycloalkyl; phenyl; substitutedphenyl in which the substitucnt is halo, lower alkyl, lower alkoxy, orlower alkylthio.

2. The compound according to claim 1 of formula (A).

3. The compound according to claim 2 wherein R is lower alkyl.

4. The compound according to claim 2 wherein R is hydrogen;5-formylxanthrone-2-carboxylic acid.

5. The compound according to claim 2 wherein R is cyclopropyl;5-cyclopropylcarbonylxanthone-2- carboxylic acid.

6. The compound according to claim 2 wherein R is methyl;5-acetylxanthone-2-carboxylic acid.-

7. The compound according to claim i of formula 8. The compoundaccording to claim 7 wherein R is lower alkyl.

9. The compound according to claim 7 wherein R is hydrogen;7-formylxanthone-Z-carboxylic acid.

10. The compound according to claim 7 wherein R is cyclopropyl;7-cyclopropylcarbonylxanthone-Z- carboxylic acid.

11. The compound according to claim 7 wherein R is methyl;7-acetylxanth0ne-2-carboxylic acid.

12. The sodium salts of the compounds according to claim l.

13. The salts according to claim 12 of formula (B).

14. The compound according to claim 13 which is sodium7-acetylxanthone-Z-carboxylate.

I TED STATES PATENT OFFICE THCATE OF CORRECTION Patent N 3,818,042(Page 1) D t d June 18, 1974 Inventor) JURG R. PFISTER, IAN T. HARRISON,JOHN H FRIED It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Column (4) line 30 Formula (4) .1 l l Colume 7, 1111s 10, R 1s R shouldread R 15 R Column 9, line 60, that portion of formula (28) i C-OH C-OHshould read 4 R R R R Column 13, line 36, "pyrazinyl, imidozolyl, shouldread pyrazinyl, pyrazolyl, imidozolyl, Column 14, line 38,"7isobutyrylxantho" should read 7-isobutyrylxantho- Column 27, line 6,"5-(1-hydroxy-lcyclophexylethyl)" should read 5-(l-hydroxyl-cyclohexylethyl) Column 34,

2. The compound according to claim 1 of formula (A).
 3. The compoundaccording to claim 2 wherein R2 is lower alkyl.
 4. The compoundaccording to claim 2 wherein R2 is hydrogen;5-formylxanthrone-2-carboxylic acid.
 5. The compound according to claim2 wherein R2 is cyclopropyl; 5-cyclopropylcarbonylxanthone-2-carboxylicacid.
 6. The compound according to claim 2 wherein R2 is methyl;5-acetylxanthone-2-carboxylic acid.
 7. The compound according to claim 1of formula (B).
 8. The compound according to claim 7 wherein R2 is loweralkyl.
 9. The compound according to claim 7 wherein R2 is hydrogen;7-formylxanthone-2-carboxylic acid.
 10. The compound according to claim7 wherein R2 is cyclopropyl; 7-cyclopropylcarbonylxanthone-2-carboxylicacid.
 11. The compound according to claim 7 wherein R2 is methyl;7-acetylxanthone-2-carboxylic acid.
 12. The sodium salts of thecompounds according to claim
 1. 13. The salts according to claim 12 offormula (B).
 14. The compound according to claim 13 which is sodium7-acetylxanthone-2-carboxylate.